IDO/HDAC dual inhibitor and pharmaceutical composition and application thereof

A solvate and drug technology, applied in the application field of drug preparation, can solve the problems of large toxic and side effects, inaccurate curative effect, etc., and achieve the effect of broad application prospects

Active Publication Date: 2020-11-10
药康众拓(北京)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Purpose of the invention: Aiming at problems such as inaccurate curative effect and relatively large toxic and side effects of existing drugs, the present invention provides an indole compound of a heterocyclic hydroxime compound A dual inhibitor of amine-2,3-dioxygenase and histone deacetylase, the present invention also provides the dual inhibitor of indole amine-2,3-dioxygenase / histone deacetylase The preparation method of, and the pharmaceutical composition containing this inhibitor, and their pharmaceutical use

Method used

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  • IDO/HDAC dual inhibitor and pharmaceutical composition and application thereof
  • IDO/HDAC dual inhibitor and pharmaceutical composition and application thereof
  • IDO/HDAC dual inhibitor and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The reaction formula is as follows;

[0031]

[0032] Step 1. 1-(4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-substituted)- 1,2,5-oxadiazole-3-substituted)-3-(3-methoxyphenyl)urea

[0033]

[0034] At 0°C, under the protection of argon, m-methoxyphenylisocyanate (14.9 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was slowly added dropwise to the raw material (30 mg, 0.0877 mmol) in tetrahydrofuran (1 mL), Warm up to room temperature and react for 16h, concentrate, add water (1mL), then add ethyl acetate (1mL), separate layers, extract the aqueous phase with ethyl acetate (2*2mL), combine the organic phases, wash with saturated brine (2mL) Washed, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain the target compound (322 mg, 66%). MS(EI,m / z):491(M + +1).

[0035]Step 2. (Z)-(N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-(3-methoxyphenyl)ureido)-1,2,5 -Oxadiazole-3-methylamide

[0036]

[0037] The above m...

Embodiment 2

[0039] (Z)-(N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-(2-methoxyphenyl)ureido)-1,2,5-oxadi Azole-3-carbamide

[0040]

[0041] The synthesis method refers to Example 1.

[0042] 1 H NMR(400MHz,DMSO):δ11.56(s,1H),9.70(s,1H),9.50(s,1H),8.95(s,1H),7.89(t,J=8.5Hz,1H), 7.12-7.06(m,1H),6.87(t,J=8.3Hz,1H),6.87(d,J=6.2Hz,1H),6.69-6.63(m,1H),3.78(s,3H)ppm. 13 C NMR (125MHz, DMSO): δ 13 C NMR (125MHz, DMSO): δ163.1, 156.3, 152.1, 149.3, 147.1, 141.3, 135.8, 128.7, 124.1, 121.2, 120.3, 113.2, 110.8, 109.3, 58.4ppm. MS (EI, m / z): 465( m + +1).

Embodiment 3

[0044] (Z)-(N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-(4-hydroxyphenyl)ureido)-1,2,5-oxadiazole- 3-methylamine

[0045]

[0046] The synthesis method refers to Example 1.

[0047] 1 H NMR(400MHz,DMSO):δ11.23(s,1H),9.88(s,1H),9.55(s,1H),9.43(s,1H),9.21(s,1H),7.38(d,J =5.3Hz, 2H), 6.93(t, J=8.2Hz, 1H), 6.87(d, J=6.2Hz, 1H), 6.75(d, J=5.3Hz, 2H)ppm. 13 C NMR(125MHz,DMSO):δ162.9,,155.3,153.1,150.2,147.5,142.1,134.6,132.2,123.5,119.5,117.5,117.8,116.8,115.2,109.9ppm.MS(EI,m / z) :451(M + +1).

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PUM

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Abstract

The invention discloses a heterocyclic hydroxamic compound with a specific structure and pharmaceutically acceptable salts, isomers, prodrugs or solvates of the heterocyclic hydroxamic compound. A pharmaceutical composition contains the heterocyclic hydroxamic compound as an active ingredient. Experiments further prove that the compound and the pharmaceutical composition have dual inhibition effects on indoleamine 2, 3-dioxygenase and histone deacetylase, and can be applied to preparation of drugs for treating diseases related to abnormal regulation of 2, 3-indoleamine dioxygenase and histonedeacetylase. The diseases comprise cancer, neurodegenerative diseases, AIDS, senile dementia, malaria, diabetes and the like, and have a wide application prospect.

Description

technical field [0001] The present invention belongs to the field of chemistry and medicine, and specifically relates to heterocyclic hydroxime compounds with specific structures and pharmaceutically acceptable salts, isomers, prodrugs or solvates thereof, as well as pharmaceutical compositions containing such compounds, and Their use in the preparation of medicines. Background technique [0002] Indoleamine-2,3-dioxygenase (IDO) is a monomeric enzyme containing heme outside the liver, which catalyzes the metabolic pathway of tryptophan kynurenine In the rate-limiting step, tryptophan is oxidized and converted into N-formylkynurenine, which is hydrolyzed to generate kynurenic acid, which then enters into the metabolic pathway of kynurenic acid to generate metabolites such as quinolinic acid and kynurenic acid. Excessive expression of IDO leads to local depletion of tryptophan, increase of metabolites such as kynuric acid, inhibits the proliferation of T cells, activates reg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08C07D413/12A61P35/00A61P35/02A61P25/00A61P25/28A61P31/18A61P33/06A61P3/10A61K31/4245A61K31/454
CPCC07D271/08C07D413/12A61P35/00A61P35/02A61P25/00A61P25/28A61P31/18A61P33/06A61P3/10Y02A50/30
Inventor 蒋晟郝海平涂正超姚和权叶科邱亚涛吴筱星张阔军张婉衡
Owner 药康众拓(北京)医药科技有限公司
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